Obesity is considered a risk for many cancers. Serum leptin levels are often elevated in obese people. Leptin acts as a mitogenic agent in many tissues; therefore, it may act to promote cancer cell growth. In fact, leptin was shown to act as a growth factor for prostate cancer cells in vitro, to induce increased migration of prostate cancer cells and expression of growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-β1), and basic fibroblast growth factor (bFGF), and to enhance prostate cancer growth. (Somasundar et al., 2004; Frankenberry et al., 2004).
Besides playing an important role in the regulation of food intake and energy consumption in the brain, leptin also acts as a potential growth stimulator in normal and neoplastic breast cancer cells. It was also shown recently to induce cell proliferation in ovarian cancer cells in vitro (Choi et al., 2004).
Leptin has been shown recently to promote T helper 1 (Th1)-cell differentiation and to modulate the onset and progression of autoimmune responses in several animal models of disease (La Cava and Matarese, 2004). If leptin's role is fundamental in Th1-mediated autoimmune diseases or inflammatory diseases, such as inflammatory bowel syndrome, then a therapeutic effect can be anticipated by blocking peripheral leptin action (Matarese et al., 2005). Leptin has also been shown to be involved in the pathogenesis of rheumatoid arthritis and in the development of experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (Peelman et al., 2005).
Consequently, both leptins and leptin antagonists have therapeutic potential. Leptin has in the past been dismissed as a potential drug for treatment of obesity, but recently has been reported to be effective in conjunction with amylin analogs (Turek et. al. 2010) or chemical chaperones (Ozcan et al. 2009). Leptin in conjunction with insulin has similarly been shown to cause improvement in mice with type 1 diabetes (Wang et al. 2010).
International Application PCT/IL2005/001250, herein incorporated by reference in its entirety as if fully disclosed herein, discloses the use of synthetic leptin antagonists in which at least two amino acid residues of the sequence LDFI of the hydrophobic binding site at the positions corresponding to positions 39-42 of the wild-type human leptin are substituted with different amino acid residues such that the site becomes less hydrophobic. The leptin antagonists are useful in treating for example metabolic syndrome, non-alcoholic steatohepatitis, atherosclerosis, type II diabetes, anorexia, cachexia, cancer, auto-inflammatory and autoimmune diseases such as multiple sclerosis, inflammatory bowel syndrome or rheumatoid arthritis.
There is an unmet need to increase the affinity of these leptin antagonists and agonists to their target receptor in order to facilitate efficient treatment at lower doses.